Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2001-02-02
2003-03-25
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
active
06537551
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an anti-tumor agent comprising a disintegrin derived from snake venom, more specifically, to an anti-tumor agent comprising Salmosin which is a novel disintegrin containing Arg-Gly-Asp (RGD) sequence and derived from venom of Korean snake,
Agkistrodon halys brevicaudus,
as an active ingredient.
BACKGROUND OF THE INVENTION
Tumor invasion and metastasis are the biological phenomena in which cancer cells lethally spread throughout the body. First, cancer cells detached from the primary site (e.g., epithelial tissue) breach the basement membrane separating them from other tissue layers. Some of these invasive cells can penetrate the basement membrane surrounding a blood vessel as well as the layer of endothelial cells lining it, which are then free to circulate via the bloodstream. Eventually, the cancer cells reach to a capillary, and adhere to and penetrate the capillary wall again, they can create a secondary tumor. Perhaps, fewer than one in 10,000 cancer cells that escape the primary site survives to form colony in another tissue (see: Erkki Ruoslahti, Scientific American, 72-77, September, 1996).
Therefore, tumor metastasis and invasion require adhesive interaction between cells and extracellular matrix (“ECM”). In the course of tumor metastasis, tumor cells can cause endothelial cells to retract, exposing the subendothelial basement membrane and allowing the tumor cells efficiently to adhere to ECM proteins of the surrounding stroma (see: Hynes, R. O., Cell, 48:549, 1987). These matrix proteins promote cell adhesion by binding to specific cell surface receptors, including a member of integrin family.
In terms of structure, each integrin is a heterodimer consisting of &agr; and &bgr; subunits which are noncovalently associated with each other. The &bgr;1 subfamily has been considered as a primary mediator of extracellular matrix adhesions. It has been reported that &bgr;1 integrins may have other functions, such as to mediate cell—cell adhesion directly (see: Larjava, H., et al., J. Cell. Biol., 110:803-815, 1990). The &bgr;2 subfamily that is found on leukocytes contains receptors mediating cell—cell interactions. The &bgr;3 subfamily includes the platelet glycoprotein IIb/IIIa complex and the vitronectin receptor, which may play an important role in the development of tumor invasiveness and malignancy (see: Albelda, S. M., et al., Cancer Res., 50:6757-6764, 1990).
The integrin receptor complex that is spanned the plasma membrane links the integral cytoskeletal network of a cell with the extracellular environment. Common or characteristic core sequences in cell adhesion molecules such as fibrinogen, vitronectin and laminin have been considered to contribute to cell adhesion and to the spread or integration of cells.
On the other hand, it was suggested that tumorigenesis and metastasis are closely associated with the biological role of integrins (see: Giancotti, F. G. and Rouslahti, E., Cell, 60:849-859, 1990; Hynes, R. O., Cell, 69:11-25, 1992; Nip, J., et al., J. Clin. Invest., 96:2096-2103, 1995).
Overexpression of fibronectin receptor &agr;5&bgr;1 suppressed the transformed phenotype of Chinese hamster ovary cells. Integrin &agr;5&bgr;1 was reduced in ras-transformed rodent cell (see: Plantefaben, L. C. and Hynes, R. O., Cell, 56:281-290, 1989) and superfibronectin that is a polymeric fibrillar form of fibronectin prevented tumor metastasis and tumor formation (see: Pasqualini, R., et al., Nature Medicine, 2:1197-1203, 1996).
Integrin &agr;v&bgr;3 is a specific marker of the most malignant cells, suggesting a crucial role of this adhesion receptor in the malignant growth of human melanoma (see: Albelda, S. M., et al., Cancer Res., 50:6757-6764, 1990). Integrin &agr;v&bgr;3 gene expression and the resulting adhesive phenotype are directly involved in the proliferation of human melanoma in vivo (see: Felding-Habermann, J. Clin. Invest., 89:2018-2022, 1992).
Angiogenesis is a biological process of forming new blood vessels as outgrowths from preexisting blood vessels (see: Folkman, J. and D'Amore, P. A., Cell, 87:1153-1155, 1996). This process plays a key role in the progression of solid tumor as well as normal development, wound healing and inflammation, and its regulation is contributed by vascular cell adhesion molecules in smooth muscle and endothelial cell (see: Nguyen, M., et al., Nature, 365:267, 1993).
The switch of angiogenic phenotype of tumor may be caused by losing balance between positive and negative modulators involved in neovascularization. Recently, it was reported that two cytokine-dependent pathways of angiogenesis were shown to exist and were defined by distinct vascular cell integrins, &agr;v&bgr;3 and &agr;v&bgr;5 that become expressed on angiogenic vascular cells where they play a critical role in angiogenesis induced by basic fibroblast growth factor (“bFGF”), tumor necrosis factor-alpha (TNF-&agr;), vascular endothelial growth factor (VEGF), and fragments of human tumors (see: Friedlander, M., et al., Science, 270:1500-502, 1995). Activation of &agr;v&bgr;3 integrin stimulates survival signal that facilitates blood vessel growth and differentiation indicating that signaling events by both cytokine and integrin receptors are closely associated with the growth of new blood vessels (see: Brooks, P. C., et al., Cell, 79:1157-1164, 1994).
On the other hand, several endogenous angiogenic inhibitors have been identified as followings: interferon-&agr;, -&ggr; (see: Friesel, R., et al., J. Cell. Biol., 104:689-696, 1987; Ezekowitz, R. A., et al., N. Engl. J. Med., 324:1456-1463, 1992); interferon-inducible protein 10(see: Angiolillo, A. L., et al., J. Exp. Med., 182:155-162, 1995; Strieter, R. M., et al., Biochem. Biophys. Res. Comm., 210:51-57, 1995); angiostatin and endostatin that specifically suppress endothelial cell proliferation (see: O'Reilly, M. S., et al., Cell, 79:315-328, 1994; O'Reilly, M. S., et al., Cell, 88:277-285, 1997); gro-&bgr; (see: Cao, Y., et al., J. Exp. Med., 182:2069-2077, 1995); the 16 kDa N-terminal fragment of prolactin (see: Clapp, C., et al., Endocrinology, 133:1292-1299, 1993); and, platelet factor-4 (see: Maione, T., et al., Science, 247:77-79, 1990; Gupta, S. K., et al., Proc. Natl. Acad. Sci., USA, 92:7799-7803, 1995).
It has been well known that disintegrins are a family of small proteins mainly derived from snake venoms (see: Niewiarowski, S., et al., Semin. Hematol., 31:289-300, 1994). Most of the disintegrins contain Arg-Gly-Asp (RGD) or Lys-Gly-Asp (KGD) sequence which is the structural motif recognized by a platelet fibrinogen receptor &agr;2b&bgr;3, and also act as a potent antagonist of several integrins including &agr;v&bgr;3 and &agr;5&bgr;1. There are several reports demonstrating that disintegrins containing the RGD sequence inhibit tumor metastasis by blocking tumor cell adhesion to ECM (see: Trikha, M. et al., Cancer Res., 54(8):4993-4998, 1994).
Integrin &agr;v&bgr;3 was identified as a marker of angiogenic blood vessels in chick embryo and human (see: Brooks, P. C., et al., Science, 264:569-571, 1994). Monoclonal antibody against &agr;v&bgr;3 was able to perturb angiogenesis by inducing apoptosis in the endothelial cells of the newly formed blood vessels. Application of synthetic peptides containing the RGD sequence that inhibit ligand binding to integrin &agr;v&bgr;3 suppressed tumor-induced angiogenesis on chick chorioallantoic membrane (“CAM”) (see: Brooks, P. C., et al., Cell, 99:1157-1164, 1994), and also suppressed the function of angiogenin which assists adhesion and diffusion of endothelial cells. Recently, triflavin, a disintegrin derived from snake venom, is reported to inhibit angiogenesis induced by TNF-&agr;. These findings suggest that disintegrins, synthetic RGD peptides and anti-&agr;v&bgr;3 monoclonal antibody may be developed as a potent anti-tumor agent.
In line with the previous reports, the present inventors isolated Salmosin derived from venom of Korean snake,
Agkistrodon halys brevicaudus,
and characterized t
Chung Kwang Hoe
Kang In-Cheol
Kim Doo-Sik
Darby & Darby
Decloux Amy
Kim Doo-Sik
Nolan Patrick J.
LandOfFree
Anti-tumor agent comprising salmosin as an active ingredient does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anti-tumor agent comprising salmosin as an active ingredient, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anti-tumor agent comprising salmosin as an active ingredient will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3023010